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Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia.

Marjamaa A, Laitinen-Forsblom P, Lahtinen AM, Viitasalo M, Toivonen L, Kontula K, Swan H - BMC Med. Genet. (2009)

Bottom Line: A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs.No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland. annukka.marjamaa@helsinki.fi

ABSTRACT

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.

Methods and results: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.

Conclusion: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

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Related in: MedlinePlus

The representative traces of single channel recordings of the RyR2 WT (A) and the RyR2 N3308S (B) at cytosolic Ca2+ concentrations of 350 nM, 700 nM and 1 μM. The channel openings are upward deflections. The open probabilities (Po) of the recorded channels are shown in the bar graph (C). No statistically significant differences were observable in the sensitivity of the channels to the cytosolic Ca2+ concentrations. Po = open probability, To = mean open time, Tc = mean closing time, c = closed state.
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Figure 4: The representative traces of single channel recordings of the RyR2 WT (A) and the RyR2 N3308S (B) at cytosolic Ca2+ concentrations of 350 nM, 700 nM and 1 μM. The channel openings are upward deflections. The open probabilities (Po) of the recorded channels are shown in the bar graph (C). No statistically significant differences were observable in the sensitivity of the channels to the cytosolic Ca2+ concentrations. Po = open probability, To = mean open time, Tc = mean closing time, c = closed state.

Mentions: Since the RyR2 N3308S mutation was associated with an atypical clinical phenotype, it was considered pertinent to study it in more detail in vitro. The representative data from the single channel recordings of the wild type RyR2 and N3308S are shown in Figure 4. The wild type RyR2 (n = 8) featured a mean open probability (Po) of 0.1 ± 0.1% at 350 nM cytosolic Ca2+ concentration, 2.6 ± 1.9% at 700 nM and 10.6 ± 6.4% at upper systolic 1 μM cytosolic Ca2+ concentration (A). The measurements of RyR2 N3308S (n = 8) showed a mean Po of 0.7 ± 0.3% at 350 nM, 2.9 ± 2.4% at 700 nM and 14.8 ± 6.9% at 1 μM cytosolic Ca2+ concentration (B). The open probabilities of the mutant channel did not differ statistically significantly from the wild type over the range of 90 nM free-[Ca2+]cis to maximal activity. In addition, the kinetics, mean open time (To) and mean closed time (Tc) of the channels were analogous.


Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia.

Marjamaa A, Laitinen-Forsblom P, Lahtinen AM, Viitasalo M, Toivonen L, Kontula K, Swan H - BMC Med. Genet. (2009)

The representative traces of single channel recordings of the RyR2 WT (A) and the RyR2 N3308S (B) at cytosolic Ca2+ concentrations of 350 nM, 700 nM and 1 μM. The channel openings are upward deflections. The open probabilities (Po) of the recorded channels are shown in the bar graph (C). No statistically significant differences were observable in the sensitivity of the channels to the cytosolic Ca2+ concentrations. Po = open probability, To = mean open time, Tc = mean closing time, c = closed state.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667497&req=5

Figure 4: The representative traces of single channel recordings of the RyR2 WT (A) and the RyR2 N3308S (B) at cytosolic Ca2+ concentrations of 350 nM, 700 nM and 1 μM. The channel openings are upward deflections. The open probabilities (Po) of the recorded channels are shown in the bar graph (C). No statistically significant differences were observable in the sensitivity of the channels to the cytosolic Ca2+ concentrations. Po = open probability, To = mean open time, Tc = mean closing time, c = closed state.
Mentions: Since the RyR2 N3308S mutation was associated with an atypical clinical phenotype, it was considered pertinent to study it in more detail in vitro. The representative data from the single channel recordings of the wild type RyR2 and N3308S are shown in Figure 4. The wild type RyR2 (n = 8) featured a mean open probability (Po) of 0.1 ± 0.1% at 350 nM cytosolic Ca2+ concentration, 2.6 ± 1.9% at 700 nM and 10.6 ± 6.4% at upper systolic 1 μM cytosolic Ca2+ concentration (A). The measurements of RyR2 N3308S (n = 8) showed a mean Po of 0.7 ± 0.3% at 350 nM, 2.9 ± 2.4% at 700 nM and 14.8 ± 6.9% at 1 μM cytosolic Ca2+ concentration (B). The open probabilities of the mutant channel did not differ statistically significantly from the wild type over the range of 90 nM free-[Ca2+]cis to maximal activity. In addition, the kinetics, mean open time (To) and mean closed time (Tc) of the channels were analogous.

Bottom Line: A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs.No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland. annukka.marjamaa@helsinki.fi

ABSTRACT

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.

Methods and results: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.

Conclusion: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

Show MeSH
Related in: MedlinePlus